Learn / Metabolism
Metabolic pathways
Every FMK pathway as a clickable map. Pick one pathway to hammer it — next step, enzyme, regulator, cofactor, and the facts that get tested (NADPH and who needs it, rate-limiting steps, deficiencies) — or set it to all pathways for a mixed drill. Every answer says which enzyme and which pathway.
Cholesterol synthesis
Acetyl-CoA → acetoacetyl-CoA → HMG-CoA → mevalonate (HMG-CoA reductase, rate-limiting, 2 NADPH, statin target) → isoprenoids → squalene → lanosterol → cholesterol. '5 steps, 1 matters most.' Regulated short-term by AMPK/insulin/glucagon phosphorylation and long-term by SREBP-2/SCAP/INSIG.
Click any metabolite on the map for its reactions. Source: FMK-05.1 Cholesterol metabolism.
Reactions
| Step | Enzyme | Cofactors | Regulation |
|---|---|---|---|
| Acetyl-CoA (cytosol) → Acetoacetyl-CoA | Thiolase | — | |
| Acetoacetyl-CoA → HMG-CoA (cytosolic) | HMG-CoA synthase (cytosolic) | + acetyl-CoA | |
| HMG-CoA (cytosolic) → Mevalonate | HMG-CoA reductase ★Statins (HMG-CoA reductase inhibition) → | 2 NADPH → 2 NADP⁺ | + Insulin; Thyroid hormone; Low sterol → SREBP-2/SCAP to Golgi → ↑ transcription of reductase and LDL receptor − Statins (competitive); AMPK phosphorylation (low energy); Glucagon, epinephrine, glucocorticoids; High sterol → INSIG retains SREBP-2 in ER and tags reductase for degradation |
| Mevalonate → Isoprenoid units (IPP) | Mevalonate kinases / decarboxylase | 3 ATP | |
| Isoprenoid units (IPP) → Squalene (C30) | Prenyl transferases → squalene synthase | — | |
| Squalene (C30) → Lanosterol | Squalene epoxidase → cyclase | NADPH, O₂ | |
| Lanosterol → Cholesterol (C27) | ~19 steps (loses 3 methyl groups) | NADPH | |
| Cholesterol (C27) → Bile acids | Cholesterol 7α-hydroxylase (CYP7A1, rate-limiting)Gallstones (cholesterol cholelithiasis) → | NADPH, O₂ | |
| Cholesterol (C27) → Vitamin D | 7-Dehydrocholesterol → UV-B (skin) → 25-OH (liver) → 1,25-(OH)₂ (kidney, 1α-hydroxylase)Vitamin D deficiency: rickets (child) / osteomalacia (adult) → | — | |
| Cholesterol (C27) → Steroid hormones | Desmolase / CYP450 side-chain cleavage (adrenal, gonads)Congenital adrenal hyperplasia (21α-hydroxylase deficiency) → | NADPH |
Conditions that live on this map
Congenital adrenal hyperplasia (21α-hydroxylase deficiency)Familial hypercholesterolemia (FH)Gallstones (cholesterol cholelithiasis)PCSK9 inhibitors (evolocumab, alirocumab)Statins (HMG-CoA reductase inhibition)Vitamin D deficiency: rickets (child) / osteomalacia (adult)
Blue pills sit on one specific arrow; grey ones are whole-pathway problems. Each opens the full condition card, which links back here with the arrow lit.
Facts worth knowing
Rate-limiting step
- Rate-limiting enzyme of bile acid synthesis — Cholesterol 7α-hydroxylase (CYP7A1)
- Rate-limiting enzyme of cholesterol synthesis — HMG-CoA reductase (The PFK-1 of cholesterol synthesis. Statins lower intracellular cholesterol → SREBP-2 → more LDL receptors — that is the actual LDL-lowering mechanism.)
Regulation
- How statins actually lower plasma LDL — Less intracellular cholesterol → SREBP-2 activation → more LDL receptors on hepatocytes → more LDL cleared
- Two independent brakes when sterol is high — INSIG holds SREBP-2/SCAP in the ER (no transcription) and marks existing HMG-CoA reductase for degradation
NADPH use
- NADPH needed for cholesterol synthesis — 2 per mevalonate (HMG-CoA reductase) plus the squalene epoxidase and demethylation steps
Cofactor
- Same intermediate, two fates: HMG-CoA — Cytosolic HMG-CoA reductase → mevalonate → cholesterol; mitochondrial HMG-CoA lyase → acetoacetate (ketone bodies)